Cardiovascular diseases are the leading cause of death in the U.S., accounting annually for more than one million deaths. Atherosclerosis is the major contributor to coronary heart disease and a primary cause of non-accidental death in Western societies. Since the prevention of atherosclerosis is an enormous unmet medical need, considerable effort has been made in defining the etiology and potential treatment of atherosclerosis and its consequences, including myocardial infarction, angina, organ failure and stroke. Despite this effort, there are many unanswered questions including how and when atherosclerotic lesions become life-threatening, the best point of intervention, and how to detect and monitor the progression of lesions.
There is widespread agreement that multiple risk factors contribute to atherosclerosis including hypertension, elevated total serum cholesterol, high levels of low density lipoprotein (xe2x80x9cLDLxe2x80x9d) cholesterol, low levels of high density lipoprotein (xe2x80x9cHDLxe2x80x9d) cholesterol, diabetes mellitus, severe obesity, and cigarette smoking. To date, treatment of atherosclerosis has been narrowly focused on treating elevated cholesterol levels and modifying lipids has become the major focus of treatment and research.
However, recent studies have indicated that 40% of deaths due to coronary disease occurred in men with total cholesterol levels of below 220 mg/dl. It is thus obvious that too great an emphasis is being placed on lipid lowering. Indeed, only 30% of patients with atherosclerosis have elevated lipid levels, indicating that other pathogenic factors are involved. A logical scenario for future therapies and preventive measures should therefore include a multidisciplinary approach consisting of diet modification, HMG-CoA reductase inhibition and novel therapies aimed directly at plaque growth and stability.
The initial lesion in atherosclerosis is the fatty streak, which arises from cholesteryl esters maintained as lipid droplets inside macrophage-derived foam cells. Macrophages down-regulate their LDL receptors and instead express mRNA and undergo new protein synthesis for a novel receptor for modified LDL. This receptor recognizes all modified forms of low-density lipoprotein and has come to be known as the macrophage scavenger receptor (xe2x80x9cMSRxe2x80x9d). If the macrophage is present in an environment that is continually generating modified LDL, it will accumulate lipid droplets of cholosteryl esters, continuing until the macrophage dies from its toxic lipid burden. The released lipid then forms the acellular necrotic core of the atherosclerotic lesion. Subsequent recruitment of fibroblasts, vascular smooth muscle cells and circulating monocytes and T-lymphocytes complete the inflammatory response and formation of the mature atherosclerotic plaque. Macrophage-derived foam cells are concentrated in the shoulders of plaques, where their secreted proteases and collagenases may contribute to plaque rupture which may lead to a fatal thrombotic event.
Plaque regression, a function of the dynamic balance among initiation, progression, stabilization and removal of plaque constituents, has been unequivocally demonstrated in humans as well as in numerous animal models. Multiple regression studies in non-human primates have shown that even relatively advanced lesions regress over time when atherogenic dietary stimuli are discontinued or pharmacological regimens are initiated.
Inhibition of lipid accumulation within macrophage-derived foam cells by utilizing MSR antagonists is expected to prevent plaque initiation, retard plaque progression, and initiate plaque regression through the process of xe2x80x9creversed cholesterol transportxe2x80x9d to acceptor HDL. Thus, MSR antagonists provide a unique approach towards the pharmacotherapy of cardiovascular diseases such as atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure, and hypercholesterolemia.
The present invention involves sulfonamidobenzanilide compounds represented by Formula (I) hereinbelow and their use as macrophage scavenger receptor (xe2x80x9cMSRxe2x80x9d) antagonists which are useful in the treatment of a variety of cardiovascular diseases including but not limited to atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.
The present invention further provides methods for antagonizing the macrophage scavenger receptor in animals, including humans, comprising administering to an animal in need of treatment an effective amount of a compound of Formula (I), indicated hereinbelow.
The present invention further provides methods of inhibiting lipid accumulation within macrophage-derived foam cells.
The compounds of the present invention are selected from Formula (I) hereinbelow: 
wherein:
R1, and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, acyl, aroyl, haloalkyl, halo, carboxy, carboalkoxy, carbamyl, alkylcarbamyl, arylcarbamyl, cyano, alkoxy, hydroxyl, phenylazo, amino, nitro, alkylamino, arylamino, arylalkylamino, acylamino, aroylamino, alkylthio, arylalkylthio, arylthio, alkysulfinyl, arylsulfinyl, arylalkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamyl, arylsulfonamido, and alkylsulfonamido;
or the R1 moiety represents a fused ring forming a benzothiophene, naphthalene, quinoline, or isoquinoline with the ring it substitutes;
or (R1)n and the ring it substitutes represents a heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine, and pyrazine, and benzo analogs thereof; and
R3 is independently selected from the group consisting of alkyl, haloalkyl, R1 aryl and R1 aralkyl, and R1 substituted heterocycles selected from the group consisting of thiophene, furan, pyridine, pyrimidine, pyrazine, imidazole, and thiazole, and benzo analogs thereof;
or R3 and the ring it substitutes represents a R1 substituted heterocycle selected from the group consisting of thiophene, furan, pyridine, pyrimidine, and pyrazine, and benzo analogs thereof.
As used herein, xe2x80x9calkylxe2x80x9d refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds. Preferred alkyl substituents are as indicated throughout. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated.
As used herein, xe2x80x9carylxe2x80x9d refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems. xe2x80x9cArylxe2x80x9d includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Preferred aryl substituents are as indicated throughout.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are, contemplated to be within the scope of the present invention.
Preferred compounds of the present invention are selected from the group consisting of:
N-Phenyl-2-(3-trifluoromethylphenylsulfonamido)benzamide,
5-Bromo-N-(3,4-dichlorophenyl)-2-(3-trifluoromethylphenylsulfonamido)benzamide,
N-(4-Chlorophenyl)-2-(2-fluorophenylsulfonamido)benzamide,
5-Bromo-N-(3-trifluoromethylphenyl)-2-(5-chloro-2-thienylsulfonamido)benzamide,
5-Chloro-N-(4-chlorophenyl)-2-(5-chloro-2- thienylsulfonamido)benzamide,
N-(3-Chloro-4-methoxyphenyl)-2-(4-methoxy phenylsulfonamido)benzamide,
N-Phenyl-2-(2-fluorophenylsulfonamido)benzamide,
N-(4-Chlorophenyl-2-(3-trifluoromethylphenylsulfonamido)benzamide,
N-Phenyl-2-(4-methoxyphenylsulfonamido)benzamide,
N-(4-Chlorophenyl-2-(3-trifluoromethylphenylsulfonamido)-4-methoxy-benzamide,
N-(3-Chloro-4-methoxyphenyl-2-(3-trifluoromethylphenylsulfonamido)-4-methoxybenzamide,
N-(3,4-Dichlorophenyl)-2-(2-fluorophenylsulfonamido)-5-methoxybenzamide,
N-(4-chlorophenyl)-2-(3-trifluoromethylphenylsulfonamido)-5-methoxybenzamide,
5-Chloro-N-(4-chlorophenyl)-2-(4-chlorophenylsulfonamido)benzamide,
5-Chloro-N-(4-chlorophenyl )-2-(3,3,3-trinfluoroethylsulfonamido)benzamide,
N-(3,4-Dichlorophenyl)-2-(phenylsulfonamido)-5-methoxybenzamide,
2-(4-Chlorophenylsulfonamido)-N-(4-ethoxycarbonylphenyl)benzamide,
5-Bromo-N-phenyl-2-(2-fluorophenylsulfonamido)benzamide;
5-Bromo-N-phenyl-2-phenylsulfonamido)benzamide;
5-Bromo-N-phenyl-2-(5-chloro-2-thienylsulfonamido)benzamide;
5-Bromo-N-(4-chlorophenyl-2-(5-chloro-2-thienylsulfonamido)benzamide;
5-Bromo-N-phenyl-2-(4-methoxyphenylsulfonamido)benzamide;
5-Bromo-N-(4chlorophenyl)-2-(2-fluorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-nitrophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(5-dimethylamino-1-naphthylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(phenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3,4-difuorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-trifluoromethylphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(n-butylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(benzylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(8-isoquinolylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(2-fluorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(2,1,3-benzothiadiazol-4-ylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-chlorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloro-4-fluorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloro-2-methylphenylsulfonamido)benzamide; and
5-Bromo-N-(4-Bromophenyl)-2-(2,4,6-trimethylphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-iodophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloropropylsulfonamido)benzamide;
N-(4-Bromophenyl)-5-chloro-2-(4-trifluoromethoxyphenyl)benzamide;
5-Bromo-N-(3-trifluoromethylphenyl)-2-(3-trifluoromethylphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-chorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloro-4-fluorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloro-2-methylphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(2,4,6-trimethylphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(2-fluorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3,4-dimethoxyphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-phenylazophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-trifluoromethylphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(2-methylphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(phenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(2-naphthylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-phenylphenysulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloropropylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(2-phenylvinyl)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-iodophenylsulfonamido)benzamide; and
5-Bromo-N-(4-Bromophenyl)-2-(4-t-butylphenylsulfonamido)benzamide.
Most preferred compounds of the present invention are selected from the group consisting of:
5-Bromo-N-(4-Bromophenyl)-2-(4-chlorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloro-4-fluorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloro-2-methylphenylsulfonamido)benzamide; and
5-Bromo-N-(4-Bromophenyl)-2-(2,4,6-trimethylphenylsulfonamido)benzamide.
Pharmaceutically acceptable salts for use when basic groups are present include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.